Prostaglandins are a family of 20 carbon, oxygen-containing fatty acids that are biochemically derived from arachidonic acid. There are approximately twenty naturally occurring prostaglandins and numerous analogs or congeners have been synthesized.
The reduction of the acid burden of the gastrointestinal tract has long been recognized as a potential therapeutic approach for the management of peptic ulcer disease. Prostaglandin E.sub.1 (PGE.sub.1), prostaglandin E.sub.2 (PGE.sub.2) and several PGE analogs or congeners have been shown to have gastric antisecretory activity in both laboratory animals and man. However, the clinical usefulness of these compounds as gastric antisecretory agents has been limited by the appearance of gastrointestinal side effects, namely nausea, vomiting, intestinal colic and diarrhea.
There is, however, another action of some prostaglandins on the gastrointestinal tract that appears to be unrelated to their ability to inhibit gastric acid secretion. This action is called "cytoprotection".
The word cytoprotection is used to describe the ability of some prostaglandins to increase the natural integrity of the gastrointestinal mucosa. The cytoprotective activity of a compound can be observed in both animals and man by noting the increased resistance of the gastrointestinal mucosa to the noxious effect of strong irritants, e.g., the ulcerogenic effects of aspirin or indomethacin. In addition to lessening the effect of nonsteroidal anti-inflammatory drugs on the gastrointestinal tract, animal studies show that cytoprotective prostaglandins prevent gastric lesions induced by oral administration of strong acids, strong bases, ethanol, hypertonic saline solutions, and even boiling water. Prostaglandins and prostaglandin analogs that exhibit a cytoprotective effect in laboratory animals have been shown to provide cytoprotection in humans. See Johansson and Bergstrom, Scand. J. Gastroenterol. suppl. Nr. 77, 17, 21-46 (1982), and the citations therein.
The cytoprotective activity of prostaglandins does not appear to be related to their ability to inhibit gastric acid secretion because:
(a) The cytoprotective unit dose is typically a small fraction of the antisecretory dose in the case of prostaglandins that exhibit gastric acid antisecretory activity. In many cases, the antisecretory ED.sub.50 is more than 100 times higher than the cytoprotective dose.
(b) Certain cytoprotective prostaglandins, e.g., 16,16-dimethyl PGA.sub.2, and 15(R)-15 methyl PGF.sub.2.beta., are not antisecretory at any dose when given orally to rats.
(c) Other antisecretory agents such as cimetidine and methscopolamine bromide, as well as antacids, are not cytoprotective in the models employed. Robert et al., Gastroenterology, 77: 433-443, (1979).
In addition, cytoprotective activity does not appear to be a property of all prostaglandins since oral administration of either PGA.sub.1 or PGD.sub.2 does not protect rats from indomethacin-induced gastric lesions. Advances in Prostaglandin and Thromboxane Research, Vol. 2, Samuelsson and Paoletti eds., Raven Press, New York, N.Y., pages 507-520, (1976).
There is no apparent general structure-activity relationship for compounds exhibiting cytoprotective activity. Cytoprotective prostaglandins have no broadly common structural configuration, therefore, it is not possible to predict which prostaglandins or prostaglandin analogs will exhibit cytoprotective activity and which will not.
Treatments to obtain a cytoprotective or antisecretory effect with prostaglandins or prostaglandin analogs have heretofore been generally by oral, enteral or parenteral administration. Exemplary oral and direct administrations are described or reported in U.S. Pat. No. 4,370,348 (rioprostil ORF-15927); Reele and Bohang Dig. Dis. Sci, 29, 390-393 (1984) [PGE.sub.2 ; 15(R),15-methyl PGE.sub.2 and 16,16-dimethyl PGE.sub.2 ]; Hunt et al., Dig. Dis. Sci., 28, 897-902 (1983) [misoprostol; SC-29333]; Robert, Viewpoints on Digestive Disease, 2, 1-4 (1979) [PGE.sub.2 ; 16,16-dimethyl PGE.sub.2 ; PGE.sub.2.beta. ]; Robert et al., Gastroenterology, 77, 433-443 (1979) [PGE.sub.2 ; 16,16-dimethyl PGE.sub.2 ; 15(S)-15-methyl PGF.sub.2.beta. ; 15(R),15-methyl PGF.sub.2.beta. and 16,16-dimethyl PGA.sub.2 ]; Johansson and Bergtrom, Scan. J. Gastroenterol., Suppl. Nr. 77, 17, 21-46 (1982) [PGE.sub.2 ; 15(R),15-methyl PGE.sub.2 ; 15(S),15-methyl PGE.sub.2 ; 16,16-dimethyl PGE.sub.2 ; and their methyl esters]; Johansson et al., Gastroenterology, 78, 479-483 (1980) [PGE.sub.2 ]; Detweiler et al., Abstract 189, Gastroenterology, 86, 1062 (1984) [rioprostil]; Shriver et al., Arzneim.-Forsch./Drug Research, 35, 839-843 (1985) [rioprostil]; and Demol et al., Arzneim. Forsch./Drug Research, 35, 861-863 (985). The above reports also include intravenous and/or subcutaneous administration (Shriver et al.; Robert et al.; and Johansson and Bergstrom) as well as application directly in the Pavlov pouch of a dog (Johansson and Bergstrom).
U.S. Pat. No. 4,198,521 describes the preparation of 15-deoxy-16-hydroxy-16-vinyl- and cyclopropyl-substituted prostanoic acids and their analogs. That patent broadly teaches that the disclosed compounds are useful as bronchodilators and hypotensive agents, and also for the control of excessive gastric secretion. U.S. Pat. No. 4,254,145 describes the use of the compounds of U.S. Pat. No. 4,198,521 in preparations applied to the skin to lower the systemic blood pressure of treated mammals.
A report by Cervoni et al., Federation Proc., 42, 157-161 (1983) discloses antihypotensive utilities of one compound, (.+-.)-15-deoxy-16-hydroxy-16 (.alpha.,.beta.) vinyl PGE.sub.2 methyl ester (CL 115,347), by oral and topical administration, that was disclosed in both of U.S. Pat. Nos. 4,198,521 and 4,254,145. A report by Birnbaum et al., Prostaglandins, 23, 185-199 (1982) provides further disclosures as to the vasodilating use of the same compound as that of the Cervoni et al. article, when that material was applied topically to the skin of laboratory mammals.